Cardiac stimulation apparatus and method for the control of hypertension

ABSTRACT

The method calls for the periodic electrical stimulation of the heart muscle to alter the ejection profile of the heart thus reducing the observed blood pressure of the patient. The therapy may be invoked by an implantable blood pressure sensor associated with a pacemaker like device.

CROSS REFERENCE TO RELATED CASES

The present case is a continuation in part application of U.S. Utilityapplication Ser. No. 11/057,279; filed Feb. 11, 2005, now abandoned,which is the utility conversion of U.S. Provisional Application60/544,112 filed Feb. 12, 2004 entitled “Antihypertensive CardiacPacing” which is incorporated herein in its entirety. Applicant claimsthe benefit of the earlier filing date of the parent application and theprovisional application for all that they contain and teach.

FIELD OF THE INVENTION

The present invention relates generally to electrical stimulation of theheart, and more particularly to stimulating the heart at times andlocations to control the patient's blood pressure as a treatment forhypertension.

BACKGROUND OF THE INVENTION

Electrical stimulation of cardiac tissue as a therapy has been known andpracticed since the 1960s. By 1967 pacemakers set a minimum heart rateand intervened to stimulate or pace the right ventricle of the heart ata fixed rate if the natural heart rate dropped below this minimum heartrate floor (VVI or “demand” pacing). This treatment, originallyprescribed for a slow heart rate or rhythm (bradycardia), was improvedwith the advent multiple chamber devices. These so-called “dual chamber”pacing devices track the prevailing heart rate and rhythm, and interveneto treat the heart with more physiologic pacing mode (VAT, DVI, DDD).Such devices are well suited to patients with intermittent rhythmdisturbances. As a group, these well known pacing modalities allow amore natural heart rate and rhythm to predominate over a wide range ofconditions.

Other heart rhythm diseases have also been treated with more specializeddevices that interact with the heart to control too-fast rhythms(tachycardia) of several differing etiologies. Antitachyardiatherapeutic devices may pace the heart rapidly to interrupt potentiallylethal arrhythmias. Implantable Cardioverter Defibrillators (ICD) withmultiple leads and several stimulus power levels have been used to treatthe lethal arrhythmias such as ventricular fibrillation, while lowerpower, multiple site pacing may aid patients in heart failure(bi-ventricular pacing) by re-synchronizing the right and leftventricles.

Throughout the history of pacing it has been observed that the act ofstimulating the heart can have a direct and substantial impact on theblood pressure of the patient. Since the earliest days, it has beennoted that ventricular pacing (VVI) may result in decreased cardiacoutput that is often associated with low blood pressure, resulting in acondition called “Pacemaker Syndrome”. Although this term is generic toa range of mechanisms and pacemaker interactions, it is a widely heldbelief that some of the impetus for development of dual chamber pacingmodalities derived from the effort to alleviate the pacemaker syndromethat was observed to be concomitant with the wide scale adoption ofsingle chamber pacemakers.

It should also be noted that more recently some implanted stimulationdevices have been proposed to “pace” or electrically stimulate thecarotid sinus baroreceptors of a patient to control blood pressure as away to treat hypertension.

Other device based approaches for reducing blood pressure through pacingare known. For example, device based therapies include pacemaker typestimulators for non-cardiac structures for treating hypertension astaught by U.S. Pat. No. 6,073,048 to Kieval which discloses a devicethat delivers stimulation to arterial baroreceptors to lower systemicblood pressure indirectly through neurogenically mediated pathways.

Pacemakers that incorporate pressure sensors are known from U.S. Pat.No. 6,522,926 to Kieval which shows a pacemaker for optimizing the AVdelay interval of a patient's heart to increase cardiac output.

SUMMARY OF THE INVENTION

In contrast to the prior art in which electrical stimulation actsprincipally to speed up or slow down the heart rate or its rhythm, thisinvention modifies observed blood pressure using electrical stimulationof the heart. The methodology may be carried out with a dedicated devicestanding alone or it may be incorporated into a conventional pacemakerthat carries out recognized and known pacing therapies. In this latterinstance the methodology and device would be a feature integrated intothe composite pacemaker. It is expected that in most implementations thedevice will be fully implanted, battery powered, and automatic in itsoperation. In this disclosure the device and antihypertensivestimulation protocol is disclosed in the context of an implanted dualchamber pacemaker providing anti-bradycardia therapy.

In the preferred embodiment, the stimulation is electrical, but thestimulation source could be from a variety of sources, including, butnot limited to mechanical, ultrasound, laser, vibration and microwave.In some embodiments, a pressure transducer signal is used to invoke theantihypertensive therapeutic stimulation and the therapy occursepisodically. In other embodiments blood pressure measurement may beused to adjust the parameters of the anti-hypertensive stimulationtherapy to arrive at an anti-hypertensive appropriate dose for thepatient. The pressure transducer may be inside the patient, in the “can”or on a lead or catheter. Alternatively, the pressure transducer may beoutside the patient and communicate with an implanted device thatcarries out the therapy, or may simply be read by the patient orclinician to adjust the operating parameters of the implanted device toarrive at the desired blood pressure level. In the simplest embodimentthe pressure measurement may be made with a conventional pressure cuff,and adjustments to the implanted device accomplished manually in amanner that is analogous to the adjustment of the dose of ananti-hypertensive medication. In one embodiment of the presentdisclosure the pressure transducer is placed across the interventricularseptum to measure the pressure in the left ventricle. In anotherembodiment the pressure measurement is made by a pressure capsule on alead or catheter in the right heart. In a further embodiment thepressure measurement is made externally to the body. In yet anotherembodiment a sensor may be placed in an artery for pressure measurement.

The antihypertensive therapy can take place while the patient is innormal sinus rhythm or the therapy may occur within a paced rhythm. Inmany embodiments the stimulation regime will take place in the rightheart at times that are early compared to the native cardiac rhythm orto the timing of an underlying anti-bradycardia pacing therapy. Thestimulation delivered to heart tissue is preferably above the capturethreshold of the heart tissue but may be above, or below the capturethreshold of the cardiac tissue at the stimulation site. The stimulationsite and pulse generator may also be used to deliver conventionalanti-bradycardia pacing therapy. Other nontraditional stimulation sitesmay be selected and may be preferable to carry out the anti-hypertensivestimulation therapy.

While several mechanisms may be involved in the beneficial modulation ofthe blood pressure by the anti-hypertensive stimulation therapy, in oneembodiment electrical energy may be applied to the right heart at timesand locations that result in diminished stroke volume accompanied by anincrease in rate to sustain cardiac output (decreasing left ventricularfilling pressure/volume); or stimulation may be applied to the septum orleft heart to reduce cardiac contractility thereby resulting in aprolonged ejection of left ventricular blood volume and reduced peakblood pressure.

It is understood that the heart exhibits several interrelatedcompensatory control mechanisms and it is expected that intermittentapplication of the antihypertensive stimulation therapy will provide thebest results for the patient. For example, anti-hypertensive therapy maybe applied for one or more beats, followed by intrinsic (oranti-bradycardia paced) beats. If additional blood pressure reduction isdesired, parameters in the implanted device may be adjusted such thatthe number of anti-hypertensive beats is increased, or the number ofintrinsic beats is decreased.

BRIEF DESCRIPTION OF THE DRAWINGS

In the several figures of the drawing identical reference numeralsindicate identical structure wherein:

FIG. 1 is divided into two panels showing the action of the right heartand left heart during the antihypertensive therapy;

FIG. 2 is divided into two panels showing the action of the normalhealthy heart during a normal sinus beat;

FIG. 3 is schematic diagram of the components of a representative devicefor carrying out the therapy;

FIG. 4 is a schematic diagram of the components of a representativedevice for carrying out the therapy;

FIG. 5 is a schematic diagram of the components of a representativedevice for carrying out the therapy;

FIG. 6 is a timing diagram representative of an alternate method ofcarrying out the therapy; and,

FIG. 7 is a timing diagram representative of an alternate method ofcarrying out the therapy, and

FIG. 8 is a timing diagram representative of an alternate method ofcarrying out the therapy;

FIG. 9 there is no FIG. 9;

FIG. 10 there is no FIG. 10;

FIG. 11A is a VOO pacing configuration used in an experiment;

FIG. 11B is a data graph of blood pressure reduction at three pacingrates as measured in connection with an experiment;

FIG. 12A is a VOO pacing configuration used in an experiment;

FIG. 12B is a data graph of blood pressure reduction at three pacingrates;

FIG. 13A is a DOO pacing configuration used in an experiment;

FIG. 13B is a data graph of blood pressure reduction at three pacingrates;

FIG. 14A is a biventricular DOO pacing configuration used in anexperiment;

FIG. 14B is a data graph of blood pressure reduction at three pacingrates;

FIG. 15A is a DOO pacing configuration used in an experiment;

FIG. 15B is a data graph of blood pressure reduction at three pacingrates;

FIG. 16A is a multisite VOO pacing configuration used in an experiment;

FIG. 16B is a data graph of blood pressure reduction at three pacingrates;

FIG. 17A is a multisite VOO pacing configuration used in an experiment;

FIG. 17B is a data graph of blood pressure reduction at three pacingrates;

FIG. 18 is a diagram showing an exemplary and illustrative heartstimulator capable of carrying out the invention;

FIG. 19 is a diagram comparing drug therapy with the inventive therapy;and,

FIG. 20 is a diagram showing how the inventive stimulation can becombined into a hybrid stimulator/drug therapy; and,

FIG. 21 is a diagram summarizing pacing configurations.

DETAILED DESCRIPTION OF THE INVENTION Cardiac Mechanics Background

If ventricular blood pressure (P) is plotted against volume (V) for theright or left ventricles a representative pressure volume (PV) loop isgenerated. The area bounded by the loop reflects the amount ofmechanical work done by the heart pumping blood during that beat.Cardiac events occur in sequence, and these correspond to variouslocations around the loop. Time proceeds counterclockwise around theloop and if beats were identical all loop points and time events wouldoverly one on another on the 2-D figure. PV loops for sequential beatsform overlapping trajectories on the figure.

FIG. 2 represents the activity of a normal healthy heart presented inthe “PV Loop paradigm”, for this reason it is labeled “prior art”. Inthe figure a separate PV loop for each “side” of the heart is shownseparately. The right heart is shown in panel A where the PV loop 10 ofthe right ventricle is seen. The left heart is depicted in panel B whichshows the PV loop 12 of the right ventricle.

Both ventricles fill easily as depicted by the lower segment 14 of theRV PV loop and the lower segment of the LV PV loop 16. Note that thesefigures show relatively little change in pressure as the ventricles fillduring diastole. In this induction segment the cardiac muscles are“relaxed”. From the electrographic viewpoint this filling occurs duringthe last part of the inter-complex interval. After activation via thesinoatrial (SA) node and the conduction system of the heart, the musclesof the ventricles contract quickly raising the pressure without muchchange in volume. The isovolumic (constant ventricular volume)contraction is seen in sections 18 and 20 respectively in panel A and Breflect this systolic phase of the heartbeat which corresponds to theelectrographic QRS complex. After a time of isovolumic contraction theheart valves open and the ejection phase begins. The ejection phasesegments 22 and 24 respectively correspond to this phase of theheartbeat. Each PV loop of the heart is completed by the isovolumicrelaxation phase of the cycle shown as segment 26 and 28 respectively inpanel A and B.

The pulsatile pumps of the right and left heart must pump the sameamount of blood on average. They are coupled by a complex network of thelungs and vascular system which are somewhat elastic, so that pressuredamping occurs in this system. The pressure and flow at the level of thecapillaries is nearly steady state while pressure differences in themajor arterial vessels are easily detected as the familiar ratio ofsystolic blood pressure (SBP) 30 to diastolic blood pressure (DBP) 32.In general a less compliant vascular network will increase the afterloadon the ventricle and the work of the ventricle is evidenced as highblood pressure at lower flow. The healthy patient, for the sameventricular work, will show more blood flow and lower peak bloodpressures.

FIG. 1 shows an implementation of the invention where aanti-hypertension stimulation intervention is provided to the rightheart. The application of the anti-hypertension stimulation causes theRight ventricle to exhibit a characteristic PV loop 50. This occurswithin a heart where the nominal PV loop without the stimulation is ofthe form seen as PV loop 52. The unmarked trajectories depict transitionPV loops from one form to another in response to anti-hypertensivestimulation. By altering the contractility of the right ventricle theresultant PV loop on the ventricular side moves from PV loop 62 to 60.The peak LV SBP (peak LV Pressure) has been reduced. The PV loops willfollow the unmarked trajectories in the figure from one loop to anotherbecause of the compliance of the vascular system and the intervention ofcompensatory mechanisms. The stimulation process is invoked in thisimplementation by detection of blood pressure above a threshold. Thethreshold is depicted in the diagram as point 70 on which corresponds toa detected trigger pressure. There are many alternative techniques fordeclaring a pressure threshold based intervention however, it isexpected that a number of consecutive beats with a measured pressure(after valve opening) that exceeds a threshold invokes the stimulationregime set forth in FIG. 6 or FIG. 7 or FIG. 8 The goal of the therapyis to move the measured blood pressure (BP) to point 72 in a number ofbeats. It is expected that the system will operate open loop that is thetherapy is invoked when a threshold is reached and the therapy occursover a fixed time or fixed number of beats.

FIG. 3 is a highly schematic diagram that corresponds to the proposedhardware device configuration. The patient's heart 100 has several leadsystems implanted. An arterial catheter 102 places a stimulationelectrode in the right atrium. On the ventricular side several leads areproposed. For example a separate transeptal pressure sensing catheter isshown as catheter 108. A right ventricular lead 104 is shown with aproximal stimulation electrode 107 and a distal stimulation electrode106. Additional stimulation locations on the left heart may be providedvia separate leads (not shown for clarity) to intrapericardial sites 109and 111. It is also possible to reach the interior of the left heart anda lead on the endocardial wall at site 113 may be useful in carrying outthe invention. These catheters are coupled to a remote electricalstimulation device 120 that is placed in the patient's chest andattached to the catheters through the cardiovascular system. This set ofstimulation catheters is sufficient to carry out traditional dualchamber stimulation modalities and may be likewise used to providestimulation regimes for carrying out the present invention. In thedevice 120 logic 110 sets several escape intervals to controlconventional pacing. This technology is well known and no detaileddescription is needed to carry out the invention. The invention isdisclosed in connection with a dual chamber DDD mode device were anatrial escape interval is defined to set a lower atrial pacing rate. Aventricular escape interval is also timed by logic 110. Although thetranseptal pressure transducer has the advantage of directly measuringleft ventricular pressure, other pressure sending methodologies may beadopted. FIG. 4 shows a pressure sensing capsule along the length of theventricular catheter 119. The capsule 121 reports right ventricularpressure to the logic 110 in the device and adjustments will need bemade to the threshold to initiate therapy.

FIG. 5 shows an external blood pressure sensor that may be aconventional sphygmomanometer cuff device. The external sensor 99telemeters the blood pressure data that is used to initial the therapyto the implanted device. Periodically blood pressure may be measured totruncate, stop or otherwise modify the therapy. In one embodiment, thepatient's blood pressure is measured by the clinician, and theparameters of the anti-hypertension stimulation are modified by theclinician to achieve the target blood pressure

In operation the transeptal pressure measurement device will provideinformation regarding the pressure in the ventricle and mostparticularly pressure in the ventricle corresponding to the time periodassociated with the minimum and maximum pressure after the heart valvesopen during the ejection period. If the measured pressure exceeds atrigger value over a long enough period of time the stimulation iscommanded to insert an additional antihypertensive stimulation therapyto drive the measured pressure to a lower value.

For example, turning to FIG. 1, if there is a pressure within the rangedelta P2 (see item 70 FIG. 1) the device may invoke a therapy attemptingto drive the measured pressure to the range delta P1 (see item 71 inFIG. 1). A successful treatment may be observed in the left ventricle asan average measured pressure moving from point 70 on loop 62 to point 72on loop 60. In essence the stimulation regime moves the heart from aloop 62 to a loop 60 via successive heart beat cycles.

There are a number of techniques that can be used to alter the PV loopof the right ventricle moving it from loop 52 to a shape more nearlysimilar to shape 50 in FIG. 1 panel A. One preferred technique is shownin FIG. 6, where the delivery of a stimulation level of energy on atrialstimulation catheter 102 preceded by multiple sub-threshold stimulationat multiple sites in the right ventricle including on the rightventricular free wall, through a multiple electrode ventricular catheter104. As a consequence of this stimulation regime it is expected that theatrial filling of the right ventricle will be reduced during thestimulated beat and one or more normal sinus beats that follow. It isexpected that the contractility of the right ventricle will be reduceddue to pre-excitation followed by stimulation to capture at least onebeat of the heart. FIG. 6 shows the interaction and integration of thehypertensive treatment with a conventional DDD pacing stimulationregime. Turning to FIG. 6 a naturally conducted sinus beat complex isshown as complex 200 comprising P, Q R, S and T segments. The P-wave isdetected by an atrial sense amplifier coupled to the RA catheter 102(FIG. 3) as seen on the atrial channel 250 of FIG. 4 as indicated bysense event 252. The conducted beat (QRS complex) is sensed by thesystem as indicated by event 254 on ventricular sensing channel 256. Inthis particular patient the transeptal pressure transducer of pressuresensing catheter 108 detects an excursion of ventricular pressuresufficient to invoke the stimulation therapy as indicated by event 260on pressure channel 258. This detected pressure event occurs within theatrial escape interval of the pacing modality selected and in responsethe device is provides a series of sub-threshold ventricular stimuli asindicated by the multiple complex 262 delivered to the multiple siteright ventricular stimulation catheter 104. After this pre-excitation ofthe right ventricle a stimulus is provided to the atrium provoking aP-wave. This AP event is shown on the atrial channel as event 264 and inthis instance it results in a conducted beat. The pre-excitation of theright ventricle results in and will be observed as a loss ofcontractility in the right ventricle resulting in a PV loop similar tothat shown as loop 50 in FIG. 1.

In FIG. 7 an alternate stimulation regime is shown for carrying out theinvention. In this instance the detection of a pressure invoking event260 is followed by atrial stimulation 261 after the next detected atrialdepolarization 263. The “late” atrial depolarization 261 provoked by thepressure sensor results in a so-called fusion beat altering the leftventricular contraction and lowering the measured blood pressure formlevel 70 in FIG. 1 to level 72 in FIG. 1.

In another embodiment, a right ventricular catheter is placed such thatthe electrode contacts the heart in the apex or on the free wall. Aright atrial catheter is also used. A timing diagram of a representativestimulation sequence to achieve the anti-hypertensive therapy is shownin FIG. 8. An intrinsic heartbeat A is shown as 300 with a native PQRand S wave (the T wave is not shown to improve clarity). The normalheart interval is shown as the interval between atrial beats P1 and P2.The normal AV delay is shown as the interval between P1 and Q1. Afterthe first heart beat 300 (Q1R1S1) shown, an intrinsic atrial contractionoccurs at P2. The anti-hypertensive stimulation algorithm stimulates theventricle early, after a short delay shown by P2 to V2. The stimulatedventricular beat 302 (Q2R2S2), being early, has lower blood flow andreduced blood pressure. For the next beat 304, the atrium is stimulatedearly, after a delay shown by P2 to A3. Stimulating the atrium earlyresults in more heart beats per unit time to maintain cardiac outputeven though the individual heartbeats are each pumping less blood atlower blood pressure. A3 causes an atrial contraction P3, which isfollowed by a normal (unstimulated) AV delay shown by P3 to Q3.Heartbeat 304 (Q3R3S3) has reduced cardiac output and reduced bloodpressure because the previous heartbeat (Q2R2S2) sent a diminishedvolume of blood to the lungs thus lowering left ventricular preload(“filling”). The next atrial event is stimulated at A4 followed by astimulated ventricular beat 306 (Q4R4S4) after a short AV delay shown bythe A4 to V4 delay. A pattern is evident from this concept. The firstheartbeat was an intrinsic, or ‘natural’ beat (A), the second heartbeatwas a transitional heart beat (B) having a normal interval but ashortened AV delay, the third heartbeat (C) had a shortened interval anda normal AV delay, and the fourth heartbeat (D) had a shortened intervaland a shortened AV delay. An anti-hypertensive stimulation algorithmwould count a certain number of A heartbeats, transition with a Bheartbeat and then alternate for a programmed number of heartbeatsalternating between C and D, ending with a C heartbeat before return tothe A heartbeat. For example: AAAABCDCDCDCAAAAB . . . etc. By decreasingthe number of As and/or increasing the number of Cs and Ds the bloodpressure reduction can be increased. Similarly, by decreasing the AVdelay, the blood pressure can be further reduced (although thestimulated A to A interval would have to be increased to maintaincardiac output). The anti-hypertensive stimulation pattern describedhere is one possibility, and is not meant to limit the scope of theinvention. It is also evident that any sequence can be generated thatwill create lowered blood pressure, that is, not all types of beats areessential for antihypertensive efficacy. The utility of the abovesequences lie in preventing tachyphylaxis, and also not stimulating theheart with too many identical hypotensive beats in sequence that mightlead to myopathic conditions. Some illustrative timing values follow.For a native heart rhythm having a P to P interval of 800 milliseconds,and an AV delay of 200 milliseconds, the stimulated A to A intervalmight be 700 milliseconds, and the stimulated AV delay might be 125milliseconds. These values may be adjusted to increase or decrease theresulting blood pressure as desired, through effects on filling andmuscle pump synchrony.

The parameters of the anti-hypertensive stimulation may be set by aclinician in a manner analogous to prescribing the dose of ananti-hypertension medication. Alternatively, an implanted blood pressuresensor may provide the input to a self-adjusting algorithm thatautomatically changes the parameters of the anti-hypertensive algorithmto achieve a target blood pressure level for the patient. Amicroprocessor based algorithm with device control may also beimplemented to manage blood pressure reduction in real time.

Experimental Results

A single pig was paced at a variety of locations and under severalparameters to provide a proof of concept for the invention. Theseresults give rise to the FIGS. 11-21. To further clarify the inventioncertain definitions are adopted as follows.

DEFINITIONS

Some terms are not consistently used with precision in the medicalliterature. For this reason and for the purposes of interpreting thisdocument the flowing definitions obtain:

Dyssynchrony is inducing a cardiac ejection cycle where the normalspatial contraction sequence is altered, either within a chamber oracross multiple cardiac chambers. It may also refer to changes incontraction within a chamber or across multiple chambers in time. Thismeans that the ejection of blood may for example be delayed, orprolonged.

Hypertension is defined as blood pressure systolic greater than 130 mmHgand/or diastolic greater than 90 mmHg.

Altered Contractility Profile is any disturbance of cardiac contractionthat changes the power or energy of the heart. It is best measured byEmax from the end systolic pressure-volume loop relationship acrossmultiple different loading conditions.

Pre Treatment Contractility Profile is the spatial and temporalcontraction of individual and combined heart chambers prior totreatment. Contractility is best measured by Emax from the end systolicpressure-volume loop relationship across multiple different loadingconditions.

Altered Ejection Profile is any disturbance of cardiac contraction,either within a chamber or across multiple chambers, that alters theresulting blood pressure as a bolus of blood is ejected from the heart.

Pre Treatment Ejection Profile is the spatial and temporal contractionof individual and combined heart chambers prior to treatment.

Congestive heart failure (CHF) is the name given to a spectrum ofclinical symptoms. Usually the heart is enlarged and has an inability tosufficiently supply the body's blood pressure and flow needs withoutgenerating abnormal intracardiac blood pressures and/or flows.

Overview

In general terms, the inventive method is the intentional reduction of apatient's blood pressure though a cardiac stimulation regime thatmodifies the synchrony between or within the chambers of the heart. Inthe simplest embodiments which form illustrative but not limitingdescriptions of the invention, pacing level stimuli are applied to theheart trough fixed leads of conventional design. The location of theleads or the timing of the stimuli is selected to alter the ejectionprofile or the contractility profile of that heartbeat. Thismodification or modulation of synchrony lowers blood pressure.

The preferred device is intended to deliver pacing level stimuli to theheart muscle to treat hypertension. In general the proposed andpreferred device will monitor blood pressure with an indwelling bloodpressure sensor and invoke a modulated synchrony therapy that results inblood pressure reduction. Experimental data and computer modeling verifythat this therapy may be used alone or in conjunction with drug therapy.

A blood pressure (BP) transducer will be exposed to systolic, diastolic,and indeed continuous blood pressures and the device may compute a meanpressure for a beat or several beats of the heart. The BP data may alsobe used to compute dP/dt and other BP measures. In most examples theexistence of hypertension is taken as a fixed BP threshold. However thisthreshold may vary as a function of time of day or measured activity. Inessence the threshold used to invoke the therapy may itself vary.

The modified therapy may be invoked on demand in response to a BPthreshold. Alternatively or in addition the therapy may be provided on aperiodic (circadian) basis, or even on a beat-by-beat interval, forexample skipping one or more beats. It may also be based on thecoincidence of a threshold BP occurring simultaneously with measuredactivity. In some embodiments the therapy may be initiated by thepatient or the physician on an acute basis. It is expected that thetherapy will not be continuous, but it will be chronic, throughout thelifetime of a hypertensive patient.

Many drugs are traditionally used for hypertension. These include ACEinhibitors, Angiotensin Receptor blockers (ARB blockers), diuretics,beta receptor blockers, alpha receptor blockers, vasodilators, calciumchannel blockers, centrally mediated antihypertensives such asmethyl-DOPA, and others. The proposed therapy will enhance theantihypertensive effects of these drugs, allowing them to work moreeffectively. The therapy can be adjusted to modulate the hypertensiveeffects of these drugs.

In many hypertensive patients, blood pressure may be reduced by theadministration of a drug that widens the QRS complex by dispersing theelectrical-myocardial conduction and contraction that may be additivewith the therapy. Candidate drugs include Tricyclic antidepressants,neuroleptics lithium procanimide lidocaine and derivatives, Class Iantiarrhyythmics, salbutamol, flecainide, sertindole, propofenone,amiodarone and others.

Illustrative Embodiments and Associated Experiments

FIG. 11 through FIG. 17 are intended to show stimulation configurationsthat can be used to carry out or promote dyssynchrony between and withincardiac chambers to control blood pressure. Panel A of each figure showsthe lead configuration and panel B shows the measured blood pressurereduction from a control measurement made in the same animal in normalsinus rhythm under otherwise similar conditions. Each panel of the datais taken at progressively higher pacing rates to capture the heart.

Thus in each instance the control for the experiment is taken in thesame animal. The pre-treatment activation profile or prêt-treatmentcontractility profile corresponds to the BP in sinus rhythm. In asimilar fashion the pre-treatment ejection profile corresponds to the BPin sinus rhythm.

FIG. 11A shows a lead 410 located in the apex of the RV coupled to apacemaker 50 (PM). Capturing the heart at pacing rates of 90, 100, and110 BPM results in the data shows in the graph of FIG. 1B. In thisfigure a reduction of BP by 16 percent is shown with no observable ratedependence.

FIG. 2A shows a lead 412 located the apex of the LV with a VVI pacingconfiguration operating effectively in a VOO modality with pacemaker450. The several pacing rates seen the graph of FIG. 12B show a −17% BPreduction without rate dependence.

FIG. 13A shows a DOO modality where the right atrium is paced by lead414 at a rate above sinus rhythm by pacemaker 450. The LV is pacedthrough lead 412 after a variously short A-V delay preventing normalsinus conduction and contractility. FIG. 3B shows that a −8% BPreduction was achieved without observable dependence on the AV intervalscan.

FIG. 14A shows a biventricular modality with VOO pacing of both the RVand the LV through leads 410 and 412. A progressive change was made tothe RV-LV pacing interval. The RR interval was above sinus rhythm andscanned as well. No discernable dependence on rate was observed howevera large −20% BP reduction was observed as seen in FIG. 14B.

FIG. 15A shows a simple DOO pacing regime carried out in DDD mode. TheAV delay was varied from 20 to 80 milliseconds and a marked reduction ofBP −22% was observed as depicted in FIG. 15B.

FIG. 16A shows a lead 410 in the LV at a first position and a secondlead 412 located in the same chamber along the septum wall. The Lva−Lvbtime interval was varied and FIG. 6B shows the −17% BP reductionachieved with this protocol.

FIG. 17A shows an intraventricular anterior-inferior placement of leads410 and 412. Burst pacing to 300 BPM showed a BP reduction of −10% asseen in FIG. 17B.

FIG. 19 reflects additional computer modeling work was performed toevaluate the effect of modified synchrony pacing or stimulationprotocols in comparison to a more conventional drug therapy.

FIG. 21 is a chart that summarizes the percent reduction based uponpacing configurations used in the experiment.

FIG. 20 reflects additional computer experimenting showing the value ofa combined drug and stimulation therapy. In the figure at a lower thannormal does of contractility reducing drug the percent change in BPreduction as a function of pacing increases dramatically. It is expectedthat combination therapy will be effective as well where the devicetherapy takes place in a patient with a “background” dose of theantihypertensive drug.

Interpretation and Benefits

FIG. 11 through FIG. 17 illustrate that any number of conventionalstimulation regimes or therapies can be invoked to modify synchronywithin or between the heart chambers. The best therapy may vary frompatient to patient and some experimentation will be required to tailor adevice for a patient. Based on the experiment it appears that thegreatest reduction in BP is achieved with RV-LV dyssynchrony stimulationas seen in FIGS. 17A and 17B.

However it should be clear that the time the stimulus is delivered orthe location of the stimulus can used to achieve the beneficialmodification of synchrony independent of lead location.

FIG. 19 shows the relationship between the inventive cardiac stimulationand more traditional pharmacology on the control of blood pressure. Line500 is the identity line corresponding to no therapy and the pretreatment and post treatment blood pressure is the “same”. Thepharmacology line 510 shows the control of blood pressure by a drugalone. For example, a patient having a pre treatment pressure of 200 mmof Hg is reduced to about 150 mm of Hg with a hypothetical drug. Thelinearity of the response however shows that the patient with anacceptable pretreatment BP of 100 mm of Hg would experience a drop to anundesirable BP of approximately 80 mm of Hg with the same drug. Thistreatment line shows that the systemic and chronic treatment of BP withdrug can have an undesirable but concomitant effect on BP.

The device therapy is seen on line 420 which offers a BP reductiontherapy which is modest and proportional to the need for therapy. Thehighly nonlinear behaviors of BP reduction with the inventivestimulation regime is of benefit to the patient since it brings agreater percent reduction benefit at the higher more pathologic BPvalues. Of considerable benefit is the fact the BP reduction occursquickly with the onset of the stimulation regime and diminishes slowlywhen the stimulation is discontinued. It is preferred to have thetherapy invoked when a threshold is exceeded and then continue for afixed period of time for example 1 hour then the therapy stops. Activitymonitors or real time clocks may be used as well.

Hardware Implementation

A representative but not limiting embodiment of a pacing device 150 tocarry out the invention is shown in FIG. 18. The drawing shows aconventional heart stimulator capable of delivering heart stimulation toleads implanted at various locations in the heart. A connection block452 allows selection of lead configurations as set forth in FIGS. 11through 17. Typically only a subset of the leads shown in the figure arerequired for carrying out the therapy. Both sensing and pacing can occurat each lead location in the heart. All rates and timing intervals areavailable in the heart stimulator. A blood pressure sensor is located ona lead. Typical locations are in the RV or remotely in other regions ofthe vasculature. In another configuration, left ventricular cavitypressure can be measured with a device placed in the right ventriclethat penetrates the ventricular septum and emerges into the leftventricular cavity. This device may also have a pressure transducer thatlies within the septal wall, and measures intra-septal force as asurrogate for contractility.

A blood pressure transducer 454 is located on either a separate bloodpressure lead or as a separate sensor 456 on a ventricular lead 410. Itis important to note that other blood pressure transduction devices maybe incorporated into the device. Although BP measurement is preferredother BP proxy measurements may be substituted within the scope of theinvention.

A blood pressure transducer is provided to measure blood pressure todetermine the existence of hypertension. The blood pressure monitoringtransducer may be located on a lead for example the RV ventricular leador a separate BP lead may be provided.

It is expected that a BP algorithm will be developed which provides a BPthreshold. The threshold may vary with time of day or patient activity.Once detected the stimulator will delivery a therapy for a treatmenttime. It is expected that the treatment time will be selected by thephysician and it may be terminated automatically or it may time out.This episodic therapy may be used alone or in conjunction with a drugregime.

Proposed Mechanism of Action

It is believed that the present invention induces a controlled andtemporary “inefficiency” in the mechanical function of the heart. Thisinefficiency is produced and controlled by altering either or all, thenormal pacing rate, the normal electrical path of ionic gradient flowthrough the heart, or dyssynchronization between the right and leftventricles. In the normal heart, initiation of the heart beat occurs inthe sinoatrial node that resides towards the epicardial surface of theright atrium close to the junction of the superior vena cava. Nodalcells have a constantly changing resting membrane potential measured inrespect to the voltage difference between the outside and inside of thecell. There are protein channels that traverse the cardiac pacemakercell membrane and allow ionic currents to flow across the membranedepending on channel opening and the diffusion gradient of various ionssuch as sodium, potassium and calcium. In the pacemaker cells, there aresodium and calcium channels that increase pacing rate by decreasingtheir resistance to ion flow from the outside to inside of the cellbased on their diffusion gradients. These ions carry a positive chargethereby inducing a decrease in the resting membrane potential and makethe cell less negative. As this process continues in time, the cellmembrane reaches an activation voltage potential whereby the calciumchannel opens completely, the doubly positively charged calcium ionsflow into the cell causing a complete depolarization. Thisdepolarization then conducts three dimensionally throughout the atrialcontractile cells. Contractile cells differ from pacemaker cells in thatthey maintain a stable resting membrane potential by allowing acontrolled amount of potassium ions to leave the cell, determined by themembrane potential. They also differ in that when they are confrontedwith either a positively charged depolarization wavefront or anartificially induced electrical stimulus, a sodium channel, instead of acalcium channel, is activated and the cell becomes depolarized. Thedepolarization in a contractile muscle cell then allows calcium ions tobe release intracellularly from the sarcoplasmic reticulum and a cellcontraction occurs.

When the depolarization wavefront of positive charges reaches theatrioventricular node, those cells become depolarized and theunidirectional wavefront continues down the “bundle of his” to the apexof the ventricles. Purkinje fibers rapidly conduct this depolarizationwavefront away from the apex and into the muscle cells of the ventriclesleading towards the base of the heart. The natural pathway of electricalconduction from the apex towards the base also results in a slightspiraling pathway. This allows the ventricular muscle to effectively andefficiently “wring” out blood from the chambers.

By implanting electrical stimulating leads in the ventricular chambers,the present invention allows for an artificial activation of theventricular multidirectional depolarization wavefront. If the electricalstimulation leads are placed in the apex of the ventricles, a closeapproximation of the natural pathway of electrical-mechanical couplingoccurs. If the pacing rate however is overdriven higher than the normalpacing rate, there will be less time for filling of blood into thechambers driven by the venous side filling pressure. In accordance withStarling's Law, less blood filling the chamber results in less stretchon the actin and myosin contractile filaments, and therefore lesscontractile force developed to eject blood from the chambers. Lessejection volume and ventricular pressure consequently results in lesssystemic blood pressure developed.

This invention also allows for de-synchronizing the right and leftventricular chambers. The stimulation leads may be placed in one or bothof the ventricular apices and stimulated in a fashion that allows onechamber to contract prior to the other. Because the right ventricleanatomically wraps around the left ventricle and produces a chambercontaining part of the left ventricle wall, a dyssynchronous contractionbetween the right and left chambers results in an inefficiency inmechanical function and resultant ejection of blood, initially from theright ventricle that results in less filling in the left ventricle andless ejection and lowered systemic blood pressure. Another aspect tothis invention is the deliberate activation of single or multiple pacingsites in the ventricle (s) at locations other than the apex. Initiationof contraction at sites towards the base of the chamber results inmyocardial contraction forces being applied to intra-chamber retrogrademovement of blood and static pressure development in the apical part ofthe chamber. This force can be directly subtracted from the overallforce developed by the ventricle to ejecting blood into the systemiccirculation, resulting in lowered blood pressure.

1. A heart muscle stimulating device for stimulating the heart 100 tomodify blood pressure comprising: a first catheter in communication withthe right ventricle (RV), coupled to said device to stimulate the rightventricle (RV), and to sense native depolarizations of the rightventricle (RV); a second catheter in communication with the right atrium(RA) coupled to said device to stimulate the right atrium (RA), and tosense native depolarizations of the right atrium (RA); a pressuresensing device providing pressure information to said heart stimulatingdevice; logic within said device responsive to said pressure sensingdevice 108 for initiating a blood pressure management stimulationprotocol in response to a pressure trigger value; said blood pressuremanagement protocol comprising delivery of right ventricular stimulationprior to the expiration of the atrial escape interval of a stimulationmode, followed promptly thereafter by the delivery of a right atrial(RA) stimulation, whereby the observed right ventricular (RV)contractility is reduced.
 2. A heart muscle stimulating device forstimulating the heart to manage blood pressure comprising: a firstcatheter in communication with the right ventricle (RV), having at leasta single electrode site, coupled to said device to stimulate the rightventricle (RV); a second catheter in communication with the right atrium(RA) coupled to said device to stimulate the right atrium (RA), and tosense native depolarizations of the right atrium (RA); a pressuresensing device providing pressure information to said heart stimulatingdevice; a blood pressure management stimulation protocol comprisingdelivery of right ventricular stimulation following a delay aftersensing a right atrial depolarization, followed thereafter by thedelivery of a right atrial (RA) stimulation, whereby blood pressure isreduced.
 3. A stimulating device that affects left ventricular functionand chamber contraction synchrony through stimulating theinterventricular septum.
 4. A method, carried out with an implantedheart muscle stimulator, for treating blood pressure disorders in apatient comprising the steps of: measuring the patient's pre treatmentblood pressure (BP), with an external or implanted sensor, correspondingto both a pretreatment cardiac ejection profile and a pretreatmentcardiac contractility profile; comparing the measured pre treatmentblood pressure with a treatment threshold; stimulating the patient'sheart with an electrical stimulus at one or more times and/or locationsto alter the cardiac ejection profile thereby reducing the measuredblood pressure from the pretreatment blood pressure value.
 5. The methodof claim 4 wherein the stimulating step comprises: placing a lead in theRV right ventricle of the heart and coupling the lead to said musclestimulator.
 6. The method of claim 4 wherein the stimulating stepcomprises: placing a lead in the LV left ventricle of the heart andcoupling the lead to said muscle stimulator.
 7. The method of claim 4wherein the stimulating step comprises: placing a lead in the LV leftventricle of the heart and placing a lead in the RV right ventricle andcoupling each of said leads to said muscle stimulator.
 8. The method ofclaim 4 wherein the stimulating step comprises: placing a first lead ata first location in the RV right ventricle of the heart and placing asecond lead at a second location different from said first location inthe RV right ventricle and coupling each of said leads to said musclestimulator.
 9. The method of claim 4 wherein the stimulating stepcomprises: placing a first lead at a first location in the LV leftventricle of the heart and placing a second lead at a second locationdifferent from said first location in the LV left ventricle and couplingeach of said leads to said muscle stimulator.
 10. The method of claim 4wherein the stimulating step comprises: placing a first lead at a firstlocation in the RA right atrium of the heart and placing a second leadat a second location in the LV left ventricle and coupling each of saidleads to said muscle stimulator.
 11. The method of claim 4 wherein thestimulating step comprises: placing a first lead at a first location inthe RA right atrium of the heart and placing a second lead at a secondlocation in the RV right ventricle and coupling each of said leads tosaid muscle stimulator.